Polycystic ovary syndrome affects approximately 5-10% of reproductive-aged women. A cardinal feature of this disorder is chronic anovulation, which is manifest clinically by irregular menstrual bleeding and is the primary cause for infertility in these women. The mechanism(s) responsible for ovulatory disruption are not well understood. While recognizing the well-documented decrease in pituitary FSH secretion, a growing body of evidence indicates that ovarian follicular function in PCOS is abnormal, which is characterized by an initial resistance to gonadotropin stimulation during ovulation induction followed by subsequent hyperresponsiveness once progressive follicle growth has been achieved. The latter consideration has particular important clinical relevance as excessive granulosa cell stimulation may lead to ovarian hyperstimulation syndrome and potential serious life-threatening complications. We have demonstrated previously, in vitro, and more recently, in vivo, that granulosa cells from PCOS ovaries exhibit greater E2 responsiveness to FSH stimulation compared to responses observed in granulosa cells of normal women. Furthermore, our assessment of FSH-stimulated E2 release in PCOS women undergoing insulin infusion suggests that granulosa cells may exhibit insulin resistant, which may result from or contribute to functional abnormalities of the follicle. The mechanisms responsible for these alterations of granulosa cell function are unknown. Of those factors, which have been shown, in vitro, to impact granulosa cell responses to FSH, estrogen, androgen, and insulin are uniquely linked to PCOS by virtue of their abnormal secretion, production, and metabolism, respectively. However, translational studies to specifically test whether these factors may be responsible for abnormal granulosa cell function in women with PCOS have not been performed. In this project, we propose to address the hypotheses that each of these factors, either alone or in combination, may be responsible for abnormal granulosa cell function in PCOS.